1. Field of the Invention
The present invention relates to polyethyleneglycol/polylactide(or polyglycolide or polycaprolactone)/polyethyleneglycol triblock copolymers with an enhanced reactivity, and a process for their preparation.
Specifically, the present invention is directed to a triblock copolymers that are obtained by the process comprising the step to synthesize a polylactide(or polyglycolide or polycaprolactone) having hydroxy groups at both ends, and the step of coupling said polylactide with polyethyleneglycol having acylhalide group of a high reactivity at one of its ends, and the process for preparing the same.
2. Description of the Prior Art
Among the different applications of degradable polymer materials, it is most actively investigated in the field of medicine. A general medical polymer is used as a permanent material with replacement of parts for a living body, whereas a biodegradable polymer is used as a transient material to help healing of the body and disappears through the body""s metabolism after completing its function. Due to these properties of the biodegradable polymer, an additional surgical operation to remove the polymer is not necessary after the body has healed. Also, as the body gradually heals, the polymer gradually degrades so that it can help newly developed tissue to function sufficiently.
Since the biodegradable polymer essentially has to have biocompatibility, only limited materials as polylactide, polyglycolide, polycaprolactone and polyethyleneglycol have been used to form the polymer. Many biodegradable polymers comprising polylactide and polyethyleneglycol have been studied in the form of block copolymers. Such polymers are comprised of hydrophobic polylactide and hydrophilic polyethyleneglycol and take the form of micelle in a solution. Also, since said polymers can make the hydrophobic polylactide hydrophilic, they can be applied widely as a bio-materials to be used as a matrix for the slow release of drugs, in tissue engineering, etc.
It was reported that block copolymer consisting of polylactide and polyethyleneglycol forms hydrogel in water and can be in a form of gel or sol by parameters of a temperature, pH, etc. so that it shows a behavior that can be used as slow releasing matrix of drug (Macromol. Chem. Phys. 198, 3385-3395 (1997)).
Most of such block copolymers, however, are in the form of a double block or triblock that is produced by a ring-open polymerization of lactide by polyethyleneglycol. Most triblocks are copolymers with a structural configuration of polylactide/polyethyleneglycol/polylactide, wherein hydrophilic polyethyleneglycol is present in the center and the hydrophobic polylactide is located at both ends.
In comparison to a block copolymer having the aforesaid configuration, a copolymer having a structural configuration of polyethyleneglycol/polylactide/polyethyleneglycol has the advantage to form harder micelle in a physical configuration when it is used as hydrogel. Furthermore, since hydrophilic polyethyleneglycol is present at both ends, its hydrophilizing effect is very great and it is expected to show a superior effect in the compatibility between hydrophobic material and hydrophilic material, and surface hydrophilization of hydrophobic material.
Because of these advantages, many efforts have been made to synthesize triblock copolymers to have a structural configuration of polyethyleneglycol/polylactide/polyethyleneglycol.
To synthesize the triblock copolymer, a method is used to couple the end groups of the synthesized polymer. In this case, the functional groups which are present at the ends of the polymer should have a very high reactivity so as to make the coupling reaction proceed quantitatively and, thus, to prepare block copolymers of the desired structure.
A generally used method is to couple the hydroxy group and the carboxyl group that are present at both ends of the polymer by use of a coupling agent such as diethyl azodicarboxylate (DEAD), triphenylphosphine (TPP), 1,3-dicyclohexylcarbodiimide (DCC) or 4-dimethylaminopyridine (DMAP). This method is generally used in coupling an organic compound. However, if it is used in the coupling reaction of the end groups in polymers, the reactivity is not high and, thus, the yield of block copolymer is very low and the catalysts used in the reaction are not easily removed.
Recently, a method is prevalently used to obtain a high reaction rate by use of a diisocyanate functional group having a high reactivity (J. Polym. Sci., Part A: Polym. Chem. 37, 751-760 (1999)). However, the block copolymer prepared by this method has the disadvantage that diusocyanate functional group with a strong toxicity remains in it.
Therefore, in preparing the block copolymer, it is very important to maintain the high reactivity of the functional groups and to connect the resulting copolymer only by non-toxic ester binding.
The present invention relates to polyethyleneglycol/polylactide(or polyglycolide or polycaprolactone)/polyethyleneglycol triblock copolymers with an enhanced reactivity, and the process for their preparation.
The present invention is specifically directed to triblock copolymers that are obtained by a process comprising the step of synthesizing a polylactide(or polyglycolide or polycaprolactone) having hydroxy groups at both ends and the step of coupling it with a polyethyleneglycol having an acylhalide group of a high reactivity at one of its ends, and a process for preparing the same.
The present invention provides a non-toxic biodegradable triblock copolymer having an ester structure and a method for preparing the same with a high yield by using a starting material having functional groups of high reactivity.
The inventors have carried out a study to achieve the object and found that triblock copolymers having an ester structure can be prepared with high yield by coupling polyethyleneglycol, having an acylhalide group of a high reactivity at one of its ends, with polylactide (or polyglycolide or polycaprolactone), having a hydroxy group at both ends.
Therefore, the invention relates to a polyethyleneglycol/polylactide (or polyglycolide or polycaprolactone)/polyethyleneglycol copolymer with a structural configuration of hydrophilicity/hydrophobicity/hydrophilicity, and a method for preparing the same.
The copolymer according to the present invention can be prepared by coupling polyethyleneglycol having acylhalide of a high reactivity at one of its ends with polylactide (or polyglycolide or polycaprolactone) having a hydroxy group at both ends in the presence of pyridine.
Specifically, the present invention provides a biodegradable triblock copolymer selected from the group consisting of copolymer of formula (1) to (4) as follows:
PEG-COO-PL-OCO-PEGxe2x80x83xe2x80x83 less than formula 1 greater than 
PEG-COO-PG-OCO-PEGxe2x80x83xe2x80x83 less than formula 2 greater than 
xe2x80x83PEG-COO-(PL/PG)-OCO-PEGxe2x80x83xe2x80x83 less than formula 3 greater than 
PEG-COO-PCL-OCO-PEGxe2x80x83xe2x80x83 less than formula 4 greater than 
In the formulas,
PEG is polyethyleneglycol,
PL is polylactide,
PG is polyglycolide,
PCL is polycaprolactone.
According to the present invention, polylactide having a hydroxy group at both ends is first synthesized by ring-open polymerization of lactide monomer in the presence of secondary alcohol. The ring-open polymerization is carried out under reduced pressure with heating by using a conventional catalyst such as stannous octotate. If xcex1,xcfx89-alkanediol such as ethylene glycol, 1,3-propanediol, 1,4-butanediol, and 1,6-hexanediol, which is a secondary alcohol, is used as a polymerization initiator, the resulting polylactide has hydroxyl groups at both ends (see scheme 1). At this time, the molecular weight of the polymer can be variously controlled depending on the added amount of the initiator and monomer. Polyglycolide and polycaprolactone can be prepared in the same manner as in the preparation of polylactide. 
Polyethyleneglycol having acylhalide group at one of its ends can be synthesized in a two-step reaction. The first step is to substitute the carboxyl group for the hydroxyl group at one of its ends, and the second step is to replace the carboxyl group with the acylhalide group. First, the hydroxy group which is present at one of its ends of monomethoxypolyethyleneglycol (m-PEG) is reacted with succinic anhydride under 4-dimethyarminopyridine (DMAP) and triethylamine (TEA) as catalysts so that the carboxyl group is introduced at the end of m-PEG (see scheme 2). If a solvent used in the reaction is nonpolar one, such as methylene chloride and chloroform, there is almost no reaction; but if a high polar solvent such as 1,4-dioxane is used, the reaction takes place very well.
Monomethoxypolyethyleneglycol (mPEG-COOH) having a carboxyl group at one of its ends is reacted with thionyl chloride to convert the carboxyl group into an acylhalide group having a high reactivity. This reaction is carried out for 3 to 4 hours at 60xc2x0 C. in methylene chloride solvent. Since the synthesized monomethoxypoly-ethyleneglycol (mPEG-COCl) having the acylhalide group at one of its ends has a high reactivity, it is very unstable. Thus, because it reacts with moisture in the air while in storage over a long period of time and is thus reconverted into m-PEG-COOH, it should be used in the coupling reaction immediately after its preparation. 
Polyethyleneglycol/polylactide/polyethyleneglycol copolymer is prepared by coupling monomethoxypolyethyleneglycol (mPEG-COCl) having the acylhalide group at one of its ends with polylactide (OH-PL-OH) having hydroxyl group at both ends as synthesized above (see scheme 3). Basic pyridine which functions as both a solvent and catalyst is used in the reaction. It removes HCl, which is produced in the reaction and plays a role in inducing the reaction toward the forward reaction. Furthermore, since addition of pyridine causes the exothermic reaction, it is gradually added with a small amount at 0xc2x0C. 
Thus prepared polyethyleneglycol/polylactide/polyethyleneglycol copolymer was obtained with a quantitative yield of more than 90%, and introduction of each functional group and coupling reaction of the end groups could be identified by means of FT-IR and 1H-NMR. Also, a high reaction rate of more than 90% was identified through an integral ratio of lactide monomer and ethyleneglycol monomer that are analyzed by 1H-NMR. In GPC (Gel Permeation Chromatography) molecular weight determination, the prepared triblock copolymer showed unimodal molecular weight distribution and had a higher molecular weight than each polylactide and polyethyleneglycol. From the results, it was found that the triblock copolymer of the complete structure was obtained.
As a result of Thermal Gravimetric Analysis (TGA), the prepared triblock copolymer showed a higher pyrolysis temperature than polylactide. Pyrolysis of polylactide has been reported to generally take place by means of an unzipping mechanism due to a hydroxy end group (Polymer, 2229-2234, 29, 1988), and pyrolysis of the triblock copolymer is presumably inhibited by replacement of hydroxy groups, which are present at both ends of polylactide, with polyethyleneglycol.
As a result of the analysis by a Differential Scanning Calorimeter (DSC), the prepared triblock copolymer had a lower crystallization temperature, a lower melting temperature and a smaller melting enthalphy than polylactide. This lowering phenomenon was enhanced proportionally to increase the molecular weight of the monomethoxypolyethyleneglycol that was added.
In determining the static contact angle which indicates hydrophilicity of the copolymer, introduction of polylactide sharply decreased the hydrophilicity of the copolymer, and as molecular weight of the polylactide become larger, the hydrophobicity of the copolymer increased.
Even in instances where polyglycolide or polycaprolactone is used in place of polylactide as a hydrophobic polymer, the triblock copolymer of a complete structure was obtained and it showed the similar thermal properties and hydrophilicity to the copolymer that was prepared by using polylactide.